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| Title | Molecular mechanism of complement inhibition by the trypanosome receptor ISG65. |
|---|---|
| Journal, issue, pages | Elife, Vol. 12, Year 2024 |
| Publish date | Apr 24, 2024 |
 Authors | Alexander D Cook / Mark Carrington / Matthew K Higgins /  |
| PubMed Abstract | African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but ...African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade. |
 External links | Elife / PubMed:38655765 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.2 - 3.4 Å |
| Structure data | EMDB-17209, PDB-8ovb:  EMDB-17219: Human Complement C3b in complex with Trypanosoma brucei ISG65  EMDB-17220: Human Complement C3b in complex with Trypanosoma brucei ISG65  EMDB-17221: Human Complement C3b  EMDB-17273: Structure of complement C3 bound to Trypanosoma brucei ISG65 |
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 Keywords |  IMMUNE SYSTEM / Complement system / parasite virulence / trypanosome surface protein / host-pathogen complex |
